Optimization of reversible electroporation for the destruction of an irregular brain tumor

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The ability to localize treatments is of great relevance to many diseases, from cancer to blood clots. The drugs used for treatment are often cytotoxic or otherwise deleterious to healthy as well as diseased tissue, and simply flooding the body is not an option. Conversely, the physiochemical properties of these drug molecules can often prevent their penetration of the cell membrane in even the targeted area. Reversible tissue electroporation serves as a method to bypass this barrier and introduce the drug into only targeted tissue. The instantaneous application of an electrical field (pulse) causes the transient formation of pores in the cell membrane that allow large molecules, including drugs, to pass into the cytosol. Such electroporation has found use clinically in electrochemotherapy, electrogenetherapy, and transdermal drug delivery. However, the introduction of reversible electroporation into body tissue can have unintended consequences that require consideration. Sensitive areas of the body, such as the brain, may be subject to overheating if the applied voltage is too high, and the electrodes must be oriented so as to minimize the penetrance of drug into healthy tissue. In vivo experimentation on animal models has several limitations, including imperfect correlation to human application, small sample sizes, and prohibitive costs. Thus predictive models are required prior to human clinical trials to ensure that minimal collateral damage is done to surrounding tissue. For this study, a two-dimensional model was developed in order to maximize death within a brain tumor while minimizing death in the surrounding healthy tissue. Given the complexity of the physics involved, the model was numerically implemented via the available software, COMSOL Multiphysics 4.3. A single pulse was applied to the domain and studied over five seconds. Pore distribution and pore size were linked to the strength of the electrical pulse implemented and the time post pulse. The reaction rate modeled the intake of drug (in this study, bleomycin) into the cell and was dependent on pore size, pore distribution, and local bleomycin concentration. Bleomycin was used for direct comparison with several other studies on electroporation that used the same agent. Using this model, it was found that for the chosen irregular tumor, thermal stress was of minimal concern as it failed to kill any cells not already killed by bleomycin. The optimization of electrode orientation, distancing and voltage application yielded a horizontal orientation with 4.8 mm between the electrodes and an applied voltage of 275 Volts, which killed 91.28% of the tumor. The application of larger voltages killed more of the tumor, but relatively more healthy cells. Sensitivity analysis on the voltage applied showed that the profile of electroporated cells followed the distribution of electric field lines, generally the 1x10^4 V/m line. It follows that there is a great deal of flexibility in the shape of the electroporated region that can be adjusted on a case-by-case basis. The goal of this model was to provide an accurate and clinically relevant simulation of reversible electroporation for tumor destruction. This is the first model that optimizes a two-electrode approach to reversible electroporation with an irregular tumor model and surrounding healthy tissue, and thus provides clinicians with finer control and understanding of this methodology for application. However further refined models must still be completed for increased predictive power; such refinements include a three dimensional model, multiple pulses, and modeling of intracranialpressure changes.

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Computer-Aided Engineering; Biomedical Processes


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